Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive investigation of the effect of the particle size, pH, biorelevant media and polymers (PVA and PVPK-25) on the solubility and dissolution of drug formulations using three model compounds with different acid-base characteristics (papaverine hydrochloride, furosemide and niflumic acid). It was demonstrated that micronization does not change the equilibrium solubility of a drug, but it results in a faster dissolution. In contrast, nanonization can improve the equilibrium solubility of a drug, but the selection of the appropriate excipient used for nanonization is essential, because out of the two used polymers, only the PVPK-25 had an increasing effect on the solubility. This phenomenon can be explained by the molecular structure of the excipients. Based on laser diffraction measurements, PVPK-25 could also inhibit the aggregation of the particles more effectively than PVA, but none of the polymers could hold the nanonized samples in the submicron range until the end of the measurements.

Lapatinib (LAP), the tyrosine kinase inhibitor drug with moderate bioavailability, was characterized in terms of physicochemical properties: acid-base characteristics, lipophilicity, and solubility. The highly lipophilic nature of the drug and its extremely low water solubility (S0=0.82 nM) limit the development of a parenteral formulation. In order to enhance solubility and bioavailability, inclusion complex formation with cyclodextrins (CDs) is a promising method of choice. Therefore, LAP-CD interactions were also studied by a multianalytical approach. The stability constants of LAP with native cyclodextrins, determined by UV spectroscopy, identified the seven-membered β-CD as the most suitable host. Continuous variation method (Job’s plot) by ¹H NMR showed a 1 : 1 stoichiometry for the complexes. The geometry of the complex was elucidated by 2D ROESY NMR measurements and molecular modeling, indicating that the partial molecular encapsulation includes the fluorophenyl ring of LAP. Phase-solubility studies with four CDs, β-CD, (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), randomly methylated-β- (RAMEB-) cyclodextrin, and sulfobutylether-β-cyclodextrin (SBE-β-CD), show an AL type diagram and highly increased solubility via CD complexation. The results are especially promising with SBE-β-CD, exerting more than 600-fold gain in solubility. The equilibrium and structural information presented herein can offer the molecular basis for an improved drug formulation with enhanced bioavailability.

The protonation macro- and microconstants have been measured for tyramine at three temperatures using potentiometry combined with UV spectroscopy. The experimentally determined zwitterion/neutral tautomerization equilibrium constant for tyramine in aqueous solution decreases with increasing temperature from log k_z = 1.03 at T = 287 K to log k _z = 0.39 at T = 310 K. Using the van't Hoff isochore, the tautomerization enthalpy was calculated as −9.3 to −13.4 kcal mol⁻¹ in the indicated temperature range. Theoretical calculations on the solvent effects have been performed using the PCM polarizable continuum dielectric solvent approach at the B3LYP/6-31G* level, and by performing Monte Carlo simulations utilizing the free energy perturbation method. The applied PCM approach, including B3LYP/6-311++G** and MP2/6-31G* single point calculations, as well, consistently favours the neutral form in aqueous solution both for tyramine and dopamine. In contrast, Monte Carlo simulations predict solvent effects that are too large and favour the zwitterionic form both for tyramine and dopamine. Neither method can predict the experimental finding that the prevalent tautomer is the zwitterion for tyramine but is the neutral form for dopamine in aqueous solution. The Monte Carlo results could be improved by finding new, appropriate net atomic charges. The present charge sets derived by fits to the PCM/B3LYP/6-31G* and PCM/B3LYP/6-311++G**//PCM/B3LYP/6-31G* molecular electrostatic potentials provide structures for the zwitterionic solutes that are too polar.

The aim of this study was to draw attention to the challenges of solubility measurement and to present new techniques and detection methods that provide more accurate results. We investigated the effect of crystal structure, pH and buffer composition on thermodynamic equilibrium solubility using two polymorphs of carvedilol (Form I and Form II) as model compounds. Measuring the solubility of carvedilol is challenging, as the literature data show extremely high standard deviation. Therefore standardized measurements were performed in the pH range 3–10, in two solutions at 25 °C: Britton–Robinson (BR) and BR with added KCl. Solid phase analysis was performed by X-ray powder diffraction and Raman spectroscopy. The measured S_pH data were compared to the theoretical Henderson–Hasselbalch (HH) curve and a perfect fit was found in the pH range 7–10. The salt formation could be observed in the acidic pH range. The counter-ion and solubility of the salt were found to be different in various buffer solutions. In situ fiber optic UV probes were used to monitor the dissolution of carvedilol polymorphs in real-time. The results showed significantly different dissolution kinetics for the polymorphs depending on the pH and the buffer solution. From the dissolution profile, the time required to reach the equilibrium was determined. In most cases, it was more than 24 hours, therefore using the standard protocol (6 hours agitation, 18 hours sedimentation) would have caused significant inaccuracy in results. In extreme cases the measured concentration after 24 hours was found to be 5 or 6 times higher than the real equilibrium solubility.

Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better understand the pH dependence of supersaturation of telmisartan (TEL) at a molecular level and find a connection between the physicochemical properties of the active pharmaceutical ingredient (API) and the ability to form supersaturated solutions of the API. Therefore, the main focus of the work was the pH-dependent thermodynamic and kinetic solubility of the model API, TEL. Based on kinetic solubility results, TEL was observed to form a supersaturated solution only in the pH range 3–8. The experimental thermodynamic solubility-pH profile shows a slight deviation from the theoretical Henderson–Hasselbalch curve, which indicates the presence of zwitterionic aggregates in the solution. Based on pK_a values and the refined solubility constants and distribution of macrospecies, the pH range where high supersaturation-capacity is observed is the same where the zwitterionic form of TEL is present. The existence of zwitterionic aggregation was confirmed experimentally in the pH range of 3 to 8 by mass spectrometry.